A systematic review of known mechanisms of hydroxyurea-induced fetal hemoglobin for treatment of sickle cell disease

Abstract

Aim: To report on molecular mechanisms of fetal hemoglobin (HbF) induction by hydroxyurea (HU) for the treatment of sickle cell disease. Study Design: Systematic review. Results: Studies have provided consistent associations between genomic variations in HbF-promoting loci and variable HbF level in response to HU. Numerous signal transduction pathways have been implicated, through the identification of key genomic variants in BCL11A, HBS1L-MYB, SAR1 or XmnI polymorphism that predispose the response to the treatment, and signal transduction pathways that modulate γ-globin expression (cAMP/cGMP; Giα/c-Jun N-terminal kinase/Jun; methylation and miRNA). Three main molecular pathways have been reported: i) Epigenetic modifications, transcriptional events and signaling pathways involved in HU-mediated response, ii) Signaling pathways involving HU-mediated response and iii) Post-transcriptional pathways (regulation by miRNAs). Conclusions: The complete picture of HU-mediated mechanisms of HbF production in Sickle Cell Disease remains elusive. Research on post-transcriptional mechanisms could lead to therapeutic targets that may minimize alterations to the cellular transcriptome.

Keywords:

• BCL11A
• fetal hemoglobin
• HBS1L-MYB and SAR1
• hydroxyurea
• molecular mechanism
• sickle cell disease

Financial & competing interests disclosure

The students’ bursaries were supported by various funding provided by the University of Cape Town, SAMRC, NHLS, NRF, FirstRand Laurie Dippenaar, and Oppenheimer Memorial Trust, South Africa. The National Institute of Health (NIH), USA, funded the report and publication of the present manuscript (grant number 1U01HG007459–01). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• The study has summarized various molecular pathways that have been reported to explain the mode of action of hydroxyurea (HU).

• Numerous signal transduction pathways have been implicated, through the identification of key genomic variants in BCL11A, HBS1L-MYB or SAR1 that predispose the response to the HU treatment in Sickle Cell Disease.

• Additional signal transduction pathways modulate γ-globin expression (cAMP/cGMP; Giα/c-Jun N-terminal kinase/Jun; methylation and miRNA).

• Three main molecular pathways have been reported:

  • – Epigenetic modifications, transcriptional events and signaling pathways involved in HU-mediated response

  • – Signaling pathways involving HU-mediated responsePost-transcriptional pathways (regulation by miRNAs)

Notes